Our laboratory has previously identified the T-box transcription factor brachyury as a driver of human carcinoma EMT. We have shown that high levels of expression of brachyury drive carcinoma cells into a mesenchymal-like phenotype, increase tumor cell motility and invasiveness in vitro, and enhance tumor cell dissemination in vivo in animal models. High levels of brachyury have been reported in various types of carcinomas, including lung, colon, prostate and breast, and our laboratory has recently demonstrated the predominant overexpression of this embryonic transcription factor in triple negative breast cancer (TNBC). Analysis of breast cancer datasets demonstrated a predominant expression of brachyury mRNA in TNBC and in basal vs luminal or HER2 molecular breast cancer subtypes. At the protein level, variable levels of brachyury expression were detected both in primary and metastatic TNBC lesions. A strong association was observed between nuclear brachyury protein expression and the stage of disease, with nuclear brachyury being more predominant in metastatic vs primary tumors. Survival analysis also demonstrated an association between high levels of brachyury in the primary tumor and poor prognosis. High levels of brachyury have been also demonstrated in small cell lung carcinomas, germ cell tumors (both embryonal and seminomas), a fraction of glioblastomas and the rare tumor type chordoma. Three brachyury-targeting cancer vaccines are currently undergoing clinical evaluation, including (1) a yeast-brachyury vaccine currently undergoing Phase II clinical evaluation in patients with chordoma; (2) an adenovirus-brachyury vaccine currently undergoing Phase I clinical evaluation; and (3) a poxviral vector-based vaccine constituted by a Modified Vaccinia Ankara (MVA) vector expressing the transgenes for brachyury and three human costimulatory molecules (B7.1, ICAM-1, and LFA-3, designated TRICOM). We recently demonstrated the ability of this vaccine to infect human dendritic cells and to activate brachyury-specific CD8+ and CD4+ T cells. A dose escalation phase I study (NCT02179515) was conducted in advanced cancer patients (n = 38), demonstrating no dose-limiting toxicities at any of the dose levels evaluated. Brachyury-specific T-cell responses were observed at all dose levels and in most patients. Phase II studies of this vaccine are currently being planned. In recent years, encouraging clinical results have been achieved in various tumor types using monoclonal antibodies that target immune checkpoints such as cytotoxic T lymphocyte associated protein-4 (CTLA-4), programmed cell death-1 (PD-1), and programmed cell death ligand-1 (PD-L1). Recent advances have revealed that EMT may also suppress antitumor immunity through upregulation of PD-L1. Our laboratory has now demonstrated the effect of TGF-B1, a cytokine known to induce EMT and to suppress antitumor immunity, on tumor PD-L1 expression in several epithelial NSCLC cell lines. We showed that upregulation of PD-L1 takes place in the context of TGF-B1-mediated mesenchymalization, a phenomenon that occurs at the transcriptional level via phosphorylation of Smad2, a key downstream effector of TGF-B signaling. Utilizing a novel bifunctional fusion protein designated M7824, which consists of an anti-PD-L1 antibody moiety linked to the extracellular domain of two TGFBRII molecules, we demonstrated that TGF-B1-dependent mesenchymalization can be prevented/reduced by M7824 treatment in NSCLC cells. Moreover, TGF-B1-mediated upregulation of PD-L1 was found to enhance the susceptibility of NSCLC cells to ADCC mediated by M7824. These findings identify upregulation of PD-L1 as an additional mechanism of TGF-B1-induced suppression of antitumor immunity, and provide further rationale for using this novel agent, M7824, to treat patients with NSCLC and potentially other malignancies. The complex signaling networks of the tumor microenvironment that facilitate tumor growth and progression toward metastatic disease are becoming a focus of potential therapeutic options. The chemokine IL-8 is overexpressed in multiple cancer types, including triple-negative breast cancer (TNBC), where it promotes the acquisition of mesenchymal features, stemness, resistance to therapies, and the recruitment of immune-suppressive cells to the tumor site. We have recently evaluated a clinical-stage monoclonal antibody that neutralizes IL-8 (HuMax-IL8) as a potential therapeutic option for TNBC. HuMax-IL8 was shown to revert mesenchymalization in claudin-low TNBC models both in vitro and in vivo as well as to significantly decrease the recruitment of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) at the tumor site, an effect substantiated when used in combination with docetaxel. In addition, HuMax-IL8 enhanced the susceptibility of claudin-low breast cancer cells to immune-mediated lysis with NK and antigen-specific T cells in vitro. These results demonstrate the multifaceted way in which neutralizing this single chemokine reverts mesenchymalization, decreases recruitment of MDSCs at the tumor site, assists in immune-mediated killing, and forms the rationale for using HuMax-IL8 in combination with chemotherapy or immune-based therapies for the treatment of TNBC. Recent studies also demonstrated that carcinoma cells that have acquired mesenchymal features may also exhibit decreased susceptibility to lysis mediated by immune effector cells, including antigen-specific CD8+ T cells, innate natural killer (NK), and lymphokine-activated killer (LAK) cells. We recently demonstrated that very high levels of brachyury expression drive the loss of the cyclin-dependent kinase inhibitor 1 (p21CIP1, p21), an event that results in decreased tumor susceptibility to immune-mediated lysis. We showed that reconstitution of p21 expression markedly increases the lysis of brachyury-high tumor cells mediated by antigen-specific CD8+ T cells, NK, and LAK cells, TNF-related apoptosis-inducing ligand, and chemotherapy. We also demonstrated that the defects in tumor cell death described in association with very high levels of brachyury could be alleviated via the use of a WEE1 inhibitor, providing rationale for the use of WEE1 inhibition in combination with brachyury-based immunotherapeutic approaches.